EP1521795B1 - Polymeres thermosensibles et gels thermoreversibles obtenus a partir de ces polymeres - Google Patents

Polymeres thermosensibles et gels thermoreversibles obtenus a partir de ces polymeres Download PDF

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EP1521795B1
EP1521795B1 EP03760030A EP03760030A EP1521795B1 EP 1521795 B1 EP1521795 B1 EP 1521795B1 EP 03760030 A EP03760030 A EP 03760030A EP 03760030 A EP03760030 A EP 03760030A EP 1521795 B1 EP1521795 B1 EP 1521795B1
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polymer
thermosensitive
peo
water
gel
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EP1521795A2 (fr
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Anne Pagnoux
Marc Dolatkhani
Patricia Chaffaux
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PolymerExpert SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/0804—Manufacture of polymers containing ionic or ionogenic groups
    • C08G18/0819—Manufacture of polymers containing ionic or ionogenic groups containing anionic or anionogenic groups
    • C08G18/0823—Manufacture of polymers containing ionic or ionogenic groups containing anionic or anionogenic groups containing carboxylate salt groups or groups forming them
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/30—Low-molecular-weight compounds
    • C08G18/32—Polyhydroxy compounds; Polyamines; Hydroxyamines
    • C08G18/3271—Hydroxyamines
    • C08G18/3275—Hydroxyamines containing two hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/30—Low-molecular-weight compounds
    • C08G18/34—Carboxylic acids; Esters thereof with monohydroxyl compounds
    • C08G18/348—Hydroxycarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/48—Polyethers
    • C08G18/4833—Polyethers containing oxyethylene units
    • C08G18/4837—Polyethers containing oxyethylene units and other oxyalkylene units
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/48—Polyethers
    • C08G18/4833—Polyethers containing oxyethylene units
    • C08G18/4837—Polyethers containing oxyethylene units and other oxyalkylene units
    • C08G18/4841—Polyethers containing oxyethylene units and other oxyalkylene units containing oxyethylene end groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/65—Low-molecular-weight compounds having active hydrogen with high-molecular-weight compounds having active hydrogen
    • C08G18/66—Compounds of groups C08G18/42, C08G18/48, or C08G18/52
    • C08G18/6666—Compounds of group C08G18/48 or C08G18/52
    • C08G18/667—Compounds of group C08G18/48 or C08G18/52 with compounds of group C08G18/32 or polyamines of C08G18/38
    • C08G18/6681—Compounds of group C08G18/48 or C08G18/52 with compounds of group C08G18/32 or polyamines of C08G18/38 with compounds of group C08G18/32 or C08G18/3271 and/or polyamines of C08G18/38
    • C08G18/6688—Compounds of group C08G18/48 or C08G18/52 with compounds of group C08G18/32 or polyamines of C08G18/38 with compounds of group C08G18/32 or C08G18/3271 and/or polyamines of C08G18/38 with compounds of group C08G18/3271
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
    • C08G18/75—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic
    • C08G18/758—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing two or more cycloaliphatic rings
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33344—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing carbamate group
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33348—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing isocyanate group
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2210/00—Compositions for preparing hydrogels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
    • C08G2650/58—Ethylene oxide or propylene oxide copolymers, e.g. pluronics

Definitions

  • the present invention relates to a thermosensitive polymer capable of forming heat-reversible gels with a high viscosity index and their preparation. It also relates to applications of these gels.
  • thermoreversible gels include, but are not limited to, therapeutic or non-therapeutic compositions, in particular cosmetic compositions, for the treatment of the human or animal body.
  • Reversible gelling compositions are defined as solutions whose variation in viscosity is related to a change in environmental conditions. When this change in viscosity occurs during a change in temperature, it will be called thermoreversible gels and the constituent polymers of the formulation are identified as “thermo-gelling polymers” or “thermosensitive polymers”. These polymers are formed of hydrophobic parts, heat-sensitive, and hydrophilic parts. The gel formation is explained by the self-association of the thermosensitive portions in hydrophobic micro-domains; the entire polymer being kept in solution by the hydrophilic segments. The viscosification properties and those of the gel are then controlled by the respective length of the different segments and by the hydrophobic / hydrophilic ratio ( LE Bromberg, Adv. Drug Delivery Reviews 31 (1998) 197-221 ).
  • thermosensitive polymers are known for forming thermoreversible gels in aqueous solution, the viscosity of said gels reversibly evolving as a function of their temperature.
  • thermosensitive polymers have hydrophobic portions capable of aggregating together to form micelles when the temperature of the medium is high to reach that of their critical solution temperature; the hydrophilic portions interconnecting said micelles. In this way, an increase in the temperature of the aqueous medium in which these heat-sensitive polymers are dissolved is capable of transforming it from a liquid state to a viscous gel state.
  • Such polymers are well known by the generic name of poloxamer. They are block copolymers of propylene oxide and ethylene oxide, or polyoxyalkylenes, which can be synthesized in particular according to the processes described in the patents US 4,188,373 and US 4,478,822 .
  • the heat-sensitive polymers thus obtained make it possible to formulate aqueous compositions having critical solution temperatures of between 24 and 40 ° C.
  • such formulations necessarily contain from 15 to 50% heat-sensitive polymers to obtain a significant variation in viscosity so that they are initially extremely viscous.
  • thermogelling polymer poly(ethylene glycol)
  • Carbopol polycarboxylic acids
  • segments of polyacrylic acids have been chemically associated with poloxamer segments.
  • the acrylic polyacid portion gives the material a greater solubility in water.
  • the presence of the hygrophilic segment promotes the solubilization of the copolymer and thus limits the phase separation. It appears that alternating copolymers of sensitive thermo- and pH-monomers quickly lose their thermo-gelling property as the level of pH-sensitive monomer increases; block copolymers are preferred.
  • thermosensitive component of the material is provided by Pluronics® polymers or poly (isopropylacrylamide) (NIPAm).
  • Pluronics® polymers or poly (isopropylacrylamide) (NIPAm) poly (isopropylacrylamide)
  • the copolymerization is carried out either by condensation reaction of the acid functions of the PAA with the modified reactive end of the Pluronic (monoamination of the hydroxy ends).
  • the Pluronic-g-poly (acrylic acid) copolymer has heat-sensitive grafts. condensation reaction between the polyacrylic acid and the poly (isopropylacrylamide), both of which are modified at one end by inter-condensable functions (amine and acid) - the Pluronic-b-poly copolymer (NIPAm) is formed by two chemically bonded blocks.
  • thermoreversible gelation of the Hoffman copolymers ( WO95 / 24430 ) is obtained with compositions of lower polymer concentrations: the formulations containing from 1 to 3% by weight of copolymer have a well-defined critical gelification temperature range, between 20 ° C and 40 ° C, for a pH range from from 4 to 8.
  • critical gelification temperature range between 20 ° C and 40 ° C
  • pH range from from 4 to 8.
  • the variation in viscosity for these compositions does not reach a decade and a phase separation in micro-domains is observed at the critical gelling temperature, which results in a opacification of the medium.
  • the syntheses are carried out in several steps: controlled modification of the terminal functions of the polymers used, condensation or copolymerization in the chain and finally separation / purification of the desired products.
  • Smart Hydrogels TM has perfect clarity before and at the point of gelation; the sol-gel transition of low concentration aqueous solutions of copolymers (1 to 5% by weight) occurs in a narrow range of temperature (10 ° C), between 25 and 40 ° C and results in a viscosity increase of approximately at least 30 times the initial viscosity.
  • the gel thus formed behaves like a viscoelastic solid and retains its viscosity regardless of the applied shear rate.
  • the bioadhesiveness of the hydrogel is limited by poor accessibility of the poly (acrylic acid) parts and the compositions have a reduced stability due to the initial oxidation of the Pluronic® polymer to create the priming radical.
  • Bromberg et al have developed novel linear block copolymers by keeping poloxamer and polyacrylic acid respectively as thermosensitive and hydrophilic compounds.
  • the originality of these copolymers is that they are composed of a central block of poloxamer modified at both ends by polyacid blocks.
  • the two ends of the poloxamer are previously functionalized with acrylic or thiol groups allowing the initiation of the radical polymerization of the acid.
  • acrylic These triblocks show a reversible gelling at body temperature (25-40 ° C.) at pH values between 3 and 13.
  • the weakly concentrated solutions (1 to 4% by weight) then undergo a viscosity increase of up to 2%. decades.
  • the synthesis route chosen is multi-stage and it is necessary to eliminate, in course or for manufacturing purposes, the residual monomers by important treatments (extraction with soxlet, dialysis, multiple precipitations ).
  • the present invention provides heat-sensitive polymers which provide not only thermoreversible physical gels with low polymer concentration, but also high viscosity viscosity thermoreversible physical gels, whose viscosity greatly increases at their critical solution temperature.
  • physical gel a gel resulting from the association of the polymer chains through the formation of non-covalent bonds, ionic type, dipolar, hydrogen bonding or hydrophobic interactions between the chains.
  • an object of the present invention is also to provide thermosensitive polymers for obtaining thermoreversible gels at temperatures substantially equal to body temperatures to formulate effective cosmetic and pharmaceutical compositions.
  • the invention relates to polymers comprising terpolymer type polymer chains consisting of polyethylene oxide (POE) and polypropylene oxide (PPO) of the form POE-PPO-POE modified at their ends by groups which may be essentially other POE-PPO-POE chains, acid segments, amine groups or POE, these chains being linked to the terpolymer chains by chemical bridges which consist of urethane bridges, urea bridges, allophanate bridges and biuret bridges. All these bridges can be present either in the same polymer chain or in different chains and, as is apparent from the following description, the proportion of these different bonds depends essentially on the operating conditions.
  • POE polyethylene oxide
  • PPO polypropylene oxide
  • the present invention provides a water-soluble heat-sensitive polymer capable of forming high-viscosity viscosity-indicating thermoreversible physical gels, characterized in that it comprises at the same time chains comprising at least one thermosensitive linear chain of polyoxyalkylene triblock constituted of polyethylene oxide (POE) blocks and polypropylene oxide (PPO) blocks, said chain being of the form POE-PPO-POE and being extended at at least one of its ends by an organic group via a carbamate bond and chains comprising at least one linear chain of polyoxyalkylene triblock type POE-PPO-POE elongated at at least one end thereof with an organic group via a urea linkage.
  • POE polyethylene oxide
  • PPO polypropylene oxide
  • thermosensitive polymer lies in the extension of the linear chain of the thermosensitive polyoxyalkylenes and in the introduction of urea groups into the polymer chain, so as to give them a higher molecular weight and to provide new functions capable of inducing additional interactions of the hydrogen bonding type.
  • the elongation is then achieved by linking the organic groups to the linear chains by carbamate and urea linkages.
  • thermosensitive polymers containing urea bridges the viscosity of the gels they formulate at their critical solution temperature is increased.
  • thermosensitive polymer comprises at least one linear chain of thermosensitive polyoxyalkylene type consisting of three blocks (polyethylene oxide-propylene oxide polyoxide-ethylene oxide) elongated at each of its two ends by an organic group via a bond carbamate or urea.
  • thermosensitive polyoxyalkylene type consisting of three blocks (polyethylene oxide-propylene oxide polyoxide-ethylene oxide) elongated at each of its two ends by an organic group via a bond carbamate or urea.
  • the molecular weight of the polymer is further increased and new groups capable of forming interactions of the hydrogen bonding type are introduced into the polymer chain, which gives an even higher viscosity to the formulated gels, at the critical temperature, without that the viscosity of the gel is important outside this critical solution temperature.
  • thermosensitive linear polyoxyalkylene triblock type chains correspond to the formula: in which, 20 ⁇ x ⁇ 120, 20 ⁇ y ⁇ 120, 20 ⁇ z ⁇ 120, and m> 0.
  • the polyoxyalkylene chain has a linear propylene oxide block each end of which is connected to an ethylene oxide block.
  • the polyoxyalkylene linear chain is symmetrical, m being equal to 1 and x being substantially equal to z. It is the ends of the chain which are connected to the organic group by carbamate and / or urea linkages.
  • said organic groups contain radicals capable of being linked to the polyoxyalkylene chains by a carbamate or urea bond and are chosen from:
  • the organic groups contain at least one of said radicals, in particular at one of its ends.
  • the radical is connected, on the one hand to the polyoxyalkylene chain by a carbamate or urea bond, and on the other hand to another molecule, also by a carbamate or urea group.
  • the organic groups contain at least one of said radicals and acid units connected to each other by carbamate or urea linkages.
  • the acidic unit is spaced from the polyoxyalkylene chain by one of said radicals, which is connected to the polyoxyalkylene chain and the acid unit by two distinct carbamate or urea bonds.
  • the organic group is capable of being constituted alternately by said radicals and by the acid units and that it is capable of extending at each of the ends of said polyoxyalkylene chain or that it is capable of gathering between they both of said poloxyalkylene chains.
  • thermosensitive polymer object of the invention is likely to see its rheological properties, not only varied depending on the temperature but also depending on the pH of the medium in which it is located.
  • the presence of an acidic group gives the thermosensitive polymer the property of bioadhesiveness.
  • said organic group contains said radicals and tertiary amine units interconnected by carbamate or urea linkages.
  • the amine functions which are capable of capturing a proton, make it possible to vary the properties of the polymer as a function of the acidity of the medium.
  • the organic group contains alternately at least one sequence: radical, amine unit, radical and acid unit, the elements of this sequence being connected in pairs by a carbamate or urea linkage.
  • said organic group contains a chain of polyethylene oxide type.
  • This polyethylene oxide chain may be spaced from the thermosensitive polyoxyalkylene chain by one of said radicals and connected thereto by a carbamate or urea bond.
  • the polyethylene oxide chain which advantageously has a molecular weight of less than 1000 is likely to be associated with acid or amine units in the organic group.
  • said organic group has branches consisting of allophanate or biuret bonds. These bonds, formed as will be explained in more detail in the description of the synthesis process, by the reaction of an isocyanate function on a carbamate or urea bond, give rise to branching through the tri-substituted nitrogen of the linkage. carbamate or urea. Thus, the radicals are likely to be connected to each other through the allophanate or biuret bonds.
  • the improved thermosensitive polymer comprises a plurality of thermosensitive triblock polyoxyalkylene linear chains interconnected by one or more organic groups via carbamate or urea bonds, or linearly, polyoxyalkylene linear chains being spaced from each other by organic groups, or branched by means of allophanate or biuret bonds.
  • organic groups may contain acid, amine or polyoxyethylene chains.
  • the present invention proposes a process for the synthesis of an improved thermosensitive polymer capable of forming high-viscosity viscosity-indicating thermoreversible physical gels and, more particularly, the polymers defined above, which process comprises the reaction of at least one thermosensitive linear polyoxyalkylene triblock polymer P having at least one hydroxy terminal function with at least one organic molecule carrying at least one isocyanate functional group so as to connect them together by carbamate or urea bonds.
  • This synthesis is carried out in a particularly simple manner in a single-stage solvent medium and without intermediate purification of the polymers P which generally contain at least traces of water, the presence of which makes it possible to introduce, during the course of the reaction, urea-type bonds. in formed chains.
  • a feature of the invention is to lengthen a thermosensitive linear polyoxyalkylene triblock polymer P having at least one hydroxy terminal function by reacting isocyanate functions on the hydroxy functions of the polymer P in the presence of water.
  • said polymer P has at least two terminal hydroxy functions so as to be elongated at each of its ends.
  • said polymer P has the generic formula: in which, 20 ⁇ x ⁇ 120, 20 ⁇ y ⁇ 120, 20 ⁇ z ⁇ 120, and m> 0.
  • m is equal to 1 and x is equal to z.
  • the organic molecule comprises two isocyanate functional groups, so that a single organic molecule can interconnect two molecules comprising hydroxyl groups via two carbamate or urea bonds obtained by condensation reaction of the isocyanate functions and the hydroxy functions, presence of water.
  • the organic molecule is chosen from:
  • said reaction is carried out in the presence of at least one other organic molecule carrying at least one hydroxyl function, advantageously two, in the presence of water.
  • the said other molecule organic is capable of being connected to the organic molecule by a carbamate or urea bond, which itself is connected to said chain of said thermosensitive linear polyoxyalkylene type P polymer.
  • said other molecule has two hydroxy functions, it is understood that one can extend said thermosensitive polymer at each of its ends, alternatively, by an organic molecule having two isocyanate functions and another molecule, the organic molecules being connected to the other organic molecules by carbamate or urea linkages.
  • said other organic molecule further comprises at least one carboxylic acid function, advantageously two.
  • said other organic molecule further comprises at least one carboxylic acid function, advantageously two.
  • said other molecule has the formula:
  • said other organic molecule advantageously comprises at least one tertiary amine function which also provides the gels formulated with the improved thermosensitive polymer with sensitivity to variations in pH.
  • said other molecule has the formula:
  • said other molecule is a monohydroxylated polyethylene oxide capable of increasing the stability and the viscosity properties of the gel containing said improved thermosensitive polymer.
  • the present invention provides an improved thermosensitive polymer having in solution a low viscosity at room temperature and capable of forming thermoreversible physical gels with a high viscosity index for temperatures above 25 ° C.
  • Its structure comprises at least one linear chain of thermosensitive triblock polyoxyalkylene type elongated at one of its ends by at least one organic group via a carbamate or urea bond. It can be obtained by a synthesis process comprising the reaction of at least one thermosensitive linear polyoxyalkylene triblock polymer P having at least one terminal hydroxy function with at least one organic molecule carrying at least one isocyanate function, in the presence of water, so as to connect them together by said carbamate or urea bond.
  • thermoreversible gel comprising at least one thermosensitive polymer according to the first object or at least one heat-sensitive polymer obtained according to a synthesis method according to the second object.
  • the gel formed is a physical gel.
  • thermoreversible gel of the invention contains from 1 to 10% by weight of said improved thermosensitive polymer and more preferably from 1 to 5% of said improved thermosensitive polymer obtained in the presence of water and thus containing urea groups.
  • the present invention proposes a pharmaceutical or non-pharmaceutical composition, in particular a cosmetic composition, intended for treating or caring for the human body, comprising a product in solution of low viscosity at temperature and capable of forming a thermoreversible physiological gel of high viscosity at temperatures above 25 ° C according to said fourth object.
  • the invention relates to a prosthetic element that can be inserted into an organ of the human body, characterized in that it comprises a heat-reversible gel according to said fourth object.
  • the present invention relates to improved linear or branched, thermosensitive hydrosoluble copolymers which have a low viscosity at room temperature in solution and which are capable of forming high viscosity index thermoreversible gels at temperatures above 26 ° C. and a method of synthesis. such polymers. In addition, it also relates to the application of such a thermoreversible gel.
  • thermosensitive water-soluble polymers are synthesized, making it possible to obtain thermoreversible gels whose viscosity increases by at least a factor of 1000 when the temperature exceeds 25 ° C. for concentrations of thermosensitive polymers in water less than 10%.
  • the synthesis of the improved thermosensitive polymers is carried out from well-known heat-sensitive copolymers: polyoxyalkylenes or poloxamers, with hydroxy functions, terminal.
  • the copolymers chosen are triblocks and have the following generic formula: in which, 20 ⁇ x ⁇ 120 and 20 ⁇ y ⁇ 120.
  • heat-sensitive polymers marketed for example under the name of Pluronics, contain 25 mol% of propylene oxide unit and allow a viscosity increase of only a factor of 10 when the temperature rises from 20 ° C. to 30 ° C. for concentrations greater than 15% in water.
  • the inventive concept of the invention lies especially in the coupling of the well-known thermosensitive polymers with organic groups whose size is smaller than that of said polymers. These couplings are likely to be obtained by reaction of diisocyanate-type organic compounds with the hydroxy functions of the thermosensitive polymer in the presence of water to form urethane and / or urea bonds as well as allophanate and / or biuret groups.
  • the processes to be carried out are simplified, since the syntheses can be carried out in one and the same reactor, the diisocyanate reacting by polycondensation with the hydroxyl functions of the thermosensitive polymers, without a step of eliminating the traces of water usually present. in polyoxyalkylene copolymers.
  • the POE-PPO-POE triblock polymer is dissolved in a solvent, preferably in butanone at a temperature of order of 70 ° C.
  • a solvent preferably in butanone
  • the di-isocyanate is introduced dropwise.
  • the catalyst is added.
  • the reaction is continued at 70 ° C. with stirring until the isocyanates have completely disappeared.
  • the advantage of the synthesis is that it is carried out in a single step in a single reactor.
  • the second advantage of this synthesis is that it is made from commercial constituents, without any additional purification treatment.
  • the POE-PPO-POE triblock copolymer is used without being dried. It then generally contains 0.3% +/- 0.05% by weight of water and this water leads during the synthesis to the formation of urea bridges.
  • the thermogelling polymers obtained are the most effective because, in addition to the urethane and allophanate bridges, there are urea and biuret bridges which can give rise to interactions of the hydrogen bonding type which add up to the interactions hydrophobic PPOs.
  • the amount of water acceptable for forming thermogelling polymers is advantageously from 0.1 to 0.6% by weight relative to the terpolymer. At 0.6% water, the viscosity of the solution of our polymer is slightly higher than that of the other improved polymer solutions, but the viscosity of the corresponding gel is also higher than that of the other gels. There is therefore a beneficial effect of water (and thereby urea groups) on the ability of polymers to gel at temperatures above 25 ° C aqueous solutions.
  • the most effective polymers are those obtained with 0.3 to 0.6% of water, introduced from the beginning of the synthesis in the reaction medium via the constituents and / or by adding water.
  • polymers can then be used alone preferably in a proportion of 3.5 to 5% by mass in aqueous solutions.
  • the improved polymer can be used at less than 3% and preferably between 1% and 2.5%. This synergistic effect is obtained with 0.05% to 1% of crosslinked polyacid.
  • the amount of polymer to be used would be at least 10% by mass to achieve the same viscosity gain.
  • the viscosity increase properties with the temperature can be adjusted according to the water concentration in the reaction medium and therefore according to the proportion of urea, biuret, allophanate and urethane groups.
  • the diisocyanates that can be used for the synthesis of the improved heat-sensitive polymers include the following compounds: which are chosen according to the kinetics of reaction and therefore the final polymer that it is desired to obtain.
  • one of the important advantages of the di-isocyanate is to be able to introduce branching into the organic groups connecting the thermosensitive polymers and also urea groups capable of forming by hydrogen bonding additional interactions. between the heat-sensitive polymer chains.
  • the polymers of the invention are either linear or branched.
  • thermosensitive polymers The structure of linearly improved thermosensitive polymers will be first described in general, and examples are then given. particular of synthetic processes. Next, improved branched heat-sensitive polymers will be described with, in the example part, particular examples.
  • thermosensitive polymer is of the form: if it is at the end of the chain or of the form: if it is in the polymer chain.
  • the group L and the heat-sensitive polymers P are connected to each other by carbamate functions, and more particularly urethane, of general form: and / or by urea functions of general form -NH-CO-NH. At the end of the chain, the group L is likely to be terminated by a nitrogen group.
  • thermosensitive polymer synthesis corresponding to the first type of polymer described above is given in Example 1.
  • the proportions of the various constituents and the Conditions of implementation are given for laboratory syntheses, but they are likely to be adapted to industrial conditions by increasing the proportions and adapting the implementation. This will be the case for all the synthesis examples described below.
  • thermosensitive polymer synthesis corresponding to this first type of polymer is described in Example 2.
  • a second type of improved thermosensitive polymer has the general formula: (AL) r1 - (PL) m , - (AL) r2 , or, (AL) r1 - [(PL) m , - (AL) r2 ] n - (PL) m , - (AL), wherein m ', r1, r2 ⁇ 1.
  • P and L correspond to the previously described structures.
  • r1 and r2 are independently of one another between 1 and 1000.
  • the symbol A corresponds to either acid blocks or tertiary amine blocks or to polyethylene oxide.
  • This second type of polymer may also contain two or all three of these blocks.
  • thermosensitive polymers is likely to be constituted by a sequence of L-type molecule and A connected to each other by carbamate functions.
  • An advantage of these organic groups is that they are ionizable and that the viscosity of the gel formulated with this second type of polymer varies with the pH of the medium.
  • Examples 3 and 4 below correspond to examples of synthesis of improved heat-sensitive polymers corresponding to this second type of polymer.
  • a third type of improved heat-sensitive polymer having branches is obtainable according to the invention. These branches are formed by reacting isocyanate functions on carbamate and / or urea functions to form allophanate bonds having the following structure: and / or biuret where the nitrogen N of the isocyanate function which has initially reacted on the hydroxy function of the polyoxyalkylene is connected to the sp 2 hybridized carbon of a second isocyanate function.
  • a general form can be given by the following formula: in which M is likely to correspond to the first or second type of improved heat-sensitive polymers as described in the examples corresponding to the two previous types of polymers.
  • R corresponds to the radical of the di-isocyate previously described and Y may correspond to an ethyl or methyl terminal function, to an amino group or to another improved thermosensitive polymer.
  • polymers are capable of being branched through the allophanate or biuret bonds, but also that they may comprise a plurality of polyoxyalkylene interconnected by organic groups which may comprise di-isocyanate alone or diisocyanate coupled with acidic, basic or other blocks.
  • thermosensitive polymers which are the subject of the present invention have the dual advantage of forming thermoreversible gels having a large increase in their viscosity for relatively low concentrations, advantageously of the order of 5%.
  • temperature ranges in which the viscosity increases are can be adjusted and can be modulated according to pH.
  • the gels are obtained from a solution containing from 1 to 10% of the polymer according to the invention, preferably from 1 to 5%, preferably from 3.5 to 5%.
  • the aqueous solution of the polymer can be obtained in two ways: from the precipitated polymer or through a solvent exchange at the end of synthesis of said polymer.
  • the precipitated and dried polymer is added in water at a pH of preferably about 7 and the dissolution is carried out at a temperature close to ambient (15-23 ° C.) during 12 hours. at 24 hours.
  • Antifoam agents may be added to limit foaming and thereby accelerate dissolution.
  • the aqueous solutions of improved thermogelling polymers thus prepared are liquid at room temperature [dynamic viscosity between 35 and 100cP (between 35.10 -3 and 0.1 Pa.s)] and gell when their temperature is between 25 ° C and 40 ° C.
  • the gelling of the solution results in an increase in viscosity of at least 3 decades (measured under a shear of 0.3 s -1 ) and the formation of a mass that can no longer flow.
  • the gel formed can be rapidly destructured if subjected to significant shear: it is shear thinning. This property is an advantage especially for cosmetic applications in which the aqueous thermogelling solution is diffused in the form of a spray. Indeed, during this operation, the polymer solution thermosensitive improved is highly sheared and therefore very liquid, then in contact with the skin the solution gels.
  • the various active ingredients and specific agents can be formulated with 3.5 to 5% of the thermosensitive polymer, in aqueous solution, at room temperature. Liquid formulations below 25 ° C can then be applied in the form of a spray on the skin, on the vaginal or nasal mucous membranes; the formulations will gel on contact. Creamy formulations can be spread on the skin and thicken when stopping friction. In these two examples, the gelling of the formulation will allow a controlled and progressive release of the active ingredients.
  • the increase in viscosity can also be used to stabilize the viscosity of sunscreens or paints. Indeed, if the heat fluidifies the products mentioned, the presence of the heat-sensitive polymer of the invention in the products makes it possible to compensate the decrease in viscosity by its gelation (or here its viscosity).
  • These polymers are formulated in aqueous solution to form pharmaceutical or non-pharmaceutical compositions, in particular cosmetic compositions, capable, in particular, of being applied at low viscosity to the body and of gelling subsequently by increasing the temperature.
  • a first example of application relates to pharmaceutical preparations comprising an improved thermosensitive polymer according to the invention in solution in water and an active ingredient.
  • This type of preparation is applied in substantially liquid form on the body and then gels so that the active ingredient is distributed over the entire application surface and is held there by the gel. Eye drops, for example, are likely to be formulated as well.
  • these preparations, containing an active principle are likely to be applied to the mucous membranes, in particular to the vaginal, nasal, stomach or esophageal mucosa.
  • a second example concerns preparations intended to be applied subcutaneously to release an active ingredient slowly or to fill spaces or cavities, for example wrinkles.
  • Breast prostheses may also be constituted by a gel formulated with a thermosensitive polymer according to the invention.
  • the prosthesis can be introduced in a liquid form which reduces the width of the incision required.
  • the plug is made by introducing into the bottom of the cavity a solution containing a polymer according to the invention in liquid form at the ambient temperature of 20 ° C and allowing it to warm to the body temperature of 37 ° C to form a plug in the bottom of the cavity.
  • Yet another example of application relates to a garment or an undergarment comprising at least a portion containing a heat-reversible gel obtained from an aqueous solution comprising an improved thermosensitive polymer according to the invention.
  • thermosensitive polymer thus synthesized corresponds to 5% of the total weight.
  • the 2-butanone contained in the mixture is removed under vacuum. The 5% mass solution of improved thermogelling polymer thus obtained is ready for use.
  • the Figure 1 illustrates the viscosity curve of the thermo-reversible gel obtained according to this first example, as a function of the temperature under a shear rate of 0.4 / s.
  • an advantage of this first embodiment of the invention lies in the increase in the viscosity of the gel of a value greater than 10 Pa.s in a temperature range between 29 and 34 ° C. with a maximum value of the viscosity for about 32 ° C.
  • thermosensitive polymer synthesis corresponding to the first type of polymer described above.
  • the solution of this improved polymer is characterized by its transparency and an increase of 5 decades in viscosity, under a shear rate of 0.01 s -1 , when its temperature reaches 35 ° C.
  • thermosensitive polymer synthesis example corresponds to the second type of polymer described above.
  • the improved thermosensitive polymer comprises polyacid blocks and tertiary amino blocks.
  • the synthesis is done in two stages.
  • a first step 3.8 ⁇ 10 -3 moles of undried Pleuronic F127 polymer containing 0.3% by weight of water are dissolved with 7.7 ⁇ 10 -3 moles of N-methyl diethanolamine in 150 ml of 2-butanone.
  • 2.3 ⁇ 10 -2 moles of 4,4'-methylene biscyclohexyl diisocyanate are added dropwise for 10 minutes under a continuous stream of nitrogen.
  • 1.2 ⁇ 10 -2 mol of tartaric acid dissolved in 2-butanone are added after six hours of reaction at 70 ° C.
  • the polycondensation continues for 2 hours until the complete disappearance of the isocyanate functions.
  • the polymer is collected either directly in aqueous phase, or after transfer of solvent or by precipitation in ether or hexane.
  • the Figure 2 illustrates the viscosity variations of the gel obtained with 5% by weight of the improved thermosensitive polymer and synthesized according to this example.
  • the Figure 2 presents 3 curves corresponding to three different values of the pH of the solution forming the gel 3.7; 5.8; and 1.8.
  • the viscosity of the gel as a function of temperature behaves similarly to the gel obtained with the improved thermosensitive polymer of the first example, except that the maximum viscosity is greater and it reaches substantially 100 Pa.s at 29 ° C under a shear rate of 0.4s -1 .
  • the viscosity curve has substantially the same shape shifted to higher temperatures since the plateau extends between 30 and 36 ° C.
  • thermosensitive polymer Thanks to the ionizable blocks of the improved thermosensitive polymer, it is possible to adjust the viscosity of the gel depending on the acidity of the solution in which it is dissolved.
  • thermosensitive polymer comprising ionizable polyacid blocks which impart a marked bioadhesive character to the gel.
  • the synthesis is done in two stages. In a first step, 3.8.10 -3 moles of undried Pleuronic F127 polymer containing 0.3% by weight of water are dissolved in 150 ml of 2-butanone. Then, 1.5 ⁇ 10 -2 moles of 4,4'-methylene biscyclohexyl diisocyanate are added dropwise for 10 minutes under a continuous stream of nitrogen. When about 81% of the isocyanate functions have been consumed, 2.9 ⁇ 10 -3 moles of 2,2- (bis-hydroxyethyl) butyric acid are added. The polycondensation continues for 24 hours at 70 ° C until the complete disappearance of the isocyanate functions.
  • the polymer is collected by precipitation in diethyl ether; the dynamic viscosity of a 5% solution of this polymer changes from 80mPa.s at room temperature to 2400 Pa.s at 35 ° C under a shear rate of 0.003s -1 .
  • the Figure 3 gives the viscosity variations of the gel obtained with 5% by weight of the thermosensitive polymer synthesized according to this example, as a function of the temperature under a shear rate of 0.3 / s.
  • thermosensitive polymer having branches; which carry segments of polyethylene oxide with a molecular weight of 750 g.
  • the synthesis takes place in two stages; a first step consisting of producing a first polymer according to the first step of Example 4 and a second step during which the monohydroxylated polyethylene oxide is introduced when only 26% of the initial isocyanate functions remain. The reaction continues for 24 hours.
  • the gel formulated with 5% of this polymer has a maximum viscosity at 37 ° C and is very dense.
  • the Figure 4 gives the viscosity curve of the thermoreversible gel obtained according to this example, as a function of the temperature under a shear rate of 0.3 / s.
  • This synthesis example makes it possible to produce an improved thermosensitive polymer having branches carrying long-chain aliphatic amines.
  • the synthesis comprises a first step identical to the first step of the preceding example and a second step in which octadecyl amine is introduced as soon as only 18% of the initial isocyanate functions remain.
  • the gel formulated with 8% of said polymer has a maximum viscosity at 37 ° C and is very dense.
  • the polymer is collected by precipitation in diethyl ether.
  • thermosensitive polymer having a higher proportion of urea groups as well as branches.
  • the synthesis takes place in two stages; a first step consisting of producing a first polymer by reaction of 3.8 ⁇ 10 -3 moles of undried F127 Pluronic polymer containing 0.3% by weight of water (7.6 ⁇ 10 -3 mole) and 0.14 g of water added (7.6 ⁇ 10 -3 mole) with 4.4 ⁇ 10 -2 mole of 4,4'-methylene biscyclohexyl diisocyanate added dropwise during 10 minutes under a continuous stream of nitrogen.
  • a tin catalyst is introduced 30 minutes after the end of the addition of the isocyanates, at a rate of 500 ppm in the mixture which is kept under reflux of the solvent.

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KR100924430B1 (ko) 2007-11-13 2009-10-29 이화여자대학교 산학협력단 온도 민감성 졸-젤 전이 ｐｐ－ｐｌｘ－ｐｐ 블록 공중합체및 이의 제조 방법
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